Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[O:34][C:35]1[CH:40]=[C:39](Cl)[N:38]=[CH:37][N:36]=1)[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][N:9]=1.[CH:51]([N:54](C(C)C)[CH2:55]C)(C)C.CNC.O1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[O:34][C:35]1[CH:40]=[C:39]([N:54]([CH3:55])[CH3:51])[N:38]=[CH:37][N:36]=1)[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][N:9]=1
Reactant: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2Oc2cc(Cl)ncn2)nc1
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2Oc2cc(N(C)C)ncn2)nc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(6-chloro-pyrimidin-4-yloxy)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (170 mg) is dissolved in toluene (5 ml), and thereto are added diisopropylethylamine (136 μl), 2.0M-dimethylamine/tetrahydrofuran solution (0.4 ml) and the mixture is stirred at 50° C. for 1 day. The reaction solution is cooled to room temperature, and thereto are added aqueous citric acid solution and ethyl acetate, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=4:1→2:1) to give ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(6-dimethylamino-pyrimidin-4-yloxy)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (115 mg). MS (m/z): 747 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:25][C@@H:26]2[C@@H:31]3[CH2:32][C@@H:28]([CH:29]=[CH:30]3)[C@@H:27]2[C:33]([NH2:35])=[O:34])=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=3[CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[NH:8][C:5]2=[N:6][CH:7]=1.[O:36]1[CH2:38][C@H:37]1[CH2:39][OH:40]>CO>[Cl:1][C:2]1[C:3]([NH:25][CH:26]2[CH:31]3[CH2:32][CH:28]([CH:29]=[CH:30]3)[CH:27]2[C:33]([NH2:35])=[O:34])=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=3[CH:19]3[CH2:20][CH2:21][N:22]([CH2:38][C@H:37]([OH:36])[CH2:39][OH:40])[CH2:23][CH2:24]3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(-c2nc3c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)c(Cl)cnc3[nH]2)c(C2CCNCC2)c1
Reactant: OC[C@@H]1CO1
Solvent: CO
Product: COc1ccc(-c2nc3c(NC4C5C=CC(C5)C4C(N)=O)c(Cl)cnc3[nH]2)c(C2CCN(C[C@H](O)CO)CC2)c1

Procedure:
(1S,2S,3R,4R)-3-[6-Chloro-2-(4-methoxy-2-piperidin-4-yl-phenyl)-3H-imidazo[4,5-b]pyridine-7-ylamino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (Compound XXX) (60 mg, 0.1 mmol) was stirred with (R)-1-oxiranyl-methanol (14.0 mg, 1.5 mmol) in methanol (5 mL) in a sealed tube overnight. The reaction was concentrated and the product purified by reverse phase chromatography (Gilson). Desired fractions were collected, combined, and lyophilized to afford the title compound as a white lyophilate (46 mg, 70%). 1H NMR (d-chloroform): 9.16 (br s, 1H), 8.03 (s, 1H), 7.65 (m, 2H), 7.30 (m, 1H), 7.02 (d, J=9 Hz, 1H), 6.95 (s, 1H), 6.32 (s, 1H), 6.17 (s, 1H), 5.52 (br m, 1H), 5.15 (m, 1H), 3.87 (m, 1H), 3.85 (s, 3H), 3.65-3.26 (m, 8H), 3.22-2.70 (m, 5H), 2.24 (d, J=9 Hz, 1H), 2.12 (m, 4H), 1.94 (m, 1H), 1.28 (s, 1H), 1.18 (d, J=5 Hz, 3H). MS: 567.17 (M+H). HPLC retention time: 1.91 minutes (G Method).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[S:5][CH:6]=1.[CH3:9][NH:10][CH3:11].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][N:10]([CH3:11])[CH3:9])[S:5][CH:6]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN(C)Cc1cc(Br)cs1
Temperature: 25 °C
Yield: 77.2 %

Procedure:
To a mixture of 4-bromothiophene-2-carbaldehyde (1.91 g, 10 mmol) and dimethylamine (2 M in THF, 7.5 mL, 15 mmol) in DCE (30 mL) was added NaBH(OAc)3 (2.65 g, 12.5 mmol), followed by AcOH (0.2 mL). After addition, the resulting mixture was stirred O/N at rt. The reaction was quenched with sat. NaHCO3 (20 mL) and brine, and was then extracted with EtOAc (100 mL+30 mL). The solvents were removed in vacuo to afford the crude title compound as a light yellow liquid (1.70 g, 77%). 1H NMR (400 MHz, CDC3) δ 7.15 (s, 1H), 6.84 (s, 1H), 3.60 (s, 2H), 2.29 (s, 6H); MS ESI 219.7 [M+H]+, calcd for [C7H10BrNS+H]+ 220.0.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:35])([CH3:34])[C@@H:11]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:12]([O:14][CH2:15][CH2:16][O:17][C:18]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:19])=[O:13])(=[O:7])=[O:6].[N-:36]=[N+:37]=[N-:38].[Na+]>CS(C)=O>[N:36]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:35])([CH3:34])[C@@H:11]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:12]([O:14][CH2:15][CH2:16][O:17][C:18]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:19])=[O:13])(=[O:7])=[O:6])=[N+:37]=[N-:38]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(COS(=O)(=O)CCCCl)[C@@H](OCc1ccccc1)C(=O)OCCOC(=O)C1CCCCC1
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(COS(=O)(=O)CCCN=[N+]=[N-])[C@@H](OCc1ccccc1)C(=O)OCCOC(=O)C1CCCCC1
Yield: 67.9 %

Procedure:
Following the general procedure for the preparation of azides of Description 16, (cyclohexylcarbonyloxy)ethyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoate (44a) (1.6 g, 3.0 mmol) dissolved in 15 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 0.65 g (10.0 mmol) of sodium azide (NaN3). After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:4) as eluent to provide 1.1 g (65% yield) of the title compound (44b) as a colorless oil. Rf=0.30 (EtOAc/Hxn=1:4). 1H NMR (400 MHz, CDCl3, both diastereomers): δ=1.04-1.06 (m, 6H), 1.19-1.30 (br. m, 3H), 1.40-1.49 (br. m, 2H), 1.51 (d, J=5.6 Hz, 3H), 1.62-1.66 (br. m, 1H), 1.70-1.78 (br. m, 2H), 1.85-1.94 (br. m, 2H), 2.01-2.08 (m, 2H), 2.24-2.37 (m, 1H), 3.09-3.15 (m, 2H), 3.43-3.47 (m, 2H), 3.81-3.83 (2s, 1H), 3.93 (d, J=8.8 Hz, 1H), 4.17-4.22 (m, 1H), 4.32-4.36 (2d, J=11.6, 11.2 Hz, 1H), 4.56-4.65 (2d, J=11.6, 11.6 Hz, 1H), 6.91-6.95 (m, 1H), 7.32-7.37 (m, 5H) ppm. MS (ESI) m/z 562.13 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:14][CH:13]=1.[CH2:23]([Br:30])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[Br-:30].[CH2:23]([N+:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][S:19]([CH3:22])(=[O:20])=[O:21])=[CH:16][CH:17]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCBr
Reactant: CS(=O)(=O)Nc1ccc(CCCC2CC3CCN2CC3)cc1
Product: CCCCCCC[N+]12CCC(CC1)CC2CCCc1ccc(NS(C)(=O)=O)cc1
Product: [Br-]

Procedure:
React N-[4-(3-(1-azabicyclo[2.2.2]oct-2-yl)propyl)phenyl]methanesulfonamide with heptyl bromide in a manner similar to Example II, Method A, to afford the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[C:8](I)=[CH:7][N:6]=[C:5]([Cl:10])[CH:4]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[C:14]([CH:22]=[CH2:23])[CH:13]=1.C(N1C2C=CC=CC=2C=CC2N=C(Cl)C(F)=CC=2C1)(=O)C>>[C:19]([N:18]1[C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][C:14]=2[CH:22]=[CH:23][C:8]2[CH:7]=[N:6][C:5]([Cl:10])=[CH:4][C:3]=2[CH2:2]1)(=[O:21])[CH3:20]
Reactant: C=Cc1cc(Cl)ccc1NC(C)=O
Reactant: Clc1cc(CBr)c(I)cn1
Agent: CC(=O)N1Cc2cc(F)c(Cl)nc2C=Cc2ccccc21
Product: CC(=O)N1Cc2cc(Cl)ncc2C=Cc2cc(Cl)ccc21

Procedure:
The title compound was prepared from 25D and 9B in two steps by a route analogous to that used for the preparation of 1D. HPLC Rt=2.836 min; LCMS Found: (M+H)+=319.
Reaction SMILES: O.Cl.[NH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.C(O[BH-](O[C:20](=O)[CH3:21])OC(=O)C)(=O)C.[Na+].[NH2:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][N:29]=[CH:28]2.C(=O)([O-])O.[Na+]>CO>[CH:20]1([CH2:21][N:3]2[CH2:8][CH2:7][CH:6]([NH:24][C:25]3[CH:26]=[C:27]4[C:31](=[CH:32][CH:33]=3)[NH:30][N:29]=[CH:28]4)[CH2:5][CH2:4]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=C1CCNCC1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: c1cc2[nH]ncc2cc1NC1CCN(CC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 19.2 %

Procedure:
4-Piperidone hydrochloride monohydrate (77 mg) and cyclohexanecarboxyaldehyde (62 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (106 mg) was added to the solution. The reaction mixture was stirred at room temperature for 18 hr. Further, 5-aminoindazole (54 mg) was added thereto, and the mixture was stirred for 30 min. A borane-pyridine complex (0.05 ml) was added thereto. The reaction mixture was stirred at room temperature for 18 hr. A saturated aqueous sodium hydrogencarbonate solution (1 ml) was then added thereto, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC [chloroform/methanol] to give the title compound (15 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[S:11]([CH3:14])(=[O:13])=[O:12])=O.[F:15][C:16]([F:28])([F:27])[C:17]1[CH:18]=[C:19]([NH:23][C:24]([NH2:26])=[O:25])[CH:20]=[CH:21][CH:22]=1.[C:29]([O:35][CH2:36][CH:37]=[CH2:38])(=[O:34])[CH2:30][C:31]([CH3:33])=O>CC(OC)(C)C>[C:7]([C:6]1[CH:9]=[CH:10][C:3]([CH:1]2[C:30]([C:29]([O:35][CH2:36][CH:37]=[CH2:38])=[O:34])=[C:31]([CH3:33])[N:23]([C:19]3[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:27])([F:28])[F:15])[CH:18]=3)[C:24](=[O:25])[NH:26]2)=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=1)#[N:8]
Reactant: NC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: C=CCOC(=O)CC(C)=O
Reactant: CS(=O)(=O)c1cc(C#N)ccc1C=O
Solvent: COC(C)(C)C
Product: C=CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1S(C)(=O)=O

Procedure:
The mixture was then diluted with MTBE (450 ml), and 4-formyl-3-(methylsulfonyl)benzonitrile (22.00 g, 105 mmol; Example 4A), 1-[3-(trifluoromethyl)phenyl]urea (21.47 g, 105 mmol) and allyl acetoacetate (22.42 g, 158 mmol) were added. The mixture was stirred under reflux overnight. Since the reaction was incomplete, the reaction mixture was concentrated by distillative removal of 350 ml of MTBE. The mixture was then heated under reflux for a further 4 h. For work-up, the solvent was removed under reduced pressure, and the residue was suspended in diethyl ether and then filtered off with suction. The solid was washed with dist. water (350 ml) and then with diethyl ether (50 ml). This gave 34.74 g (64% of theory) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11][C@H:10](C(O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P([N:35]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.C(O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[NH2:35][C@@H:10]1[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][C@H:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11]1
Reactant: COC(=O)[C@@H]1C[C@H](C(=O)O)CN(C(=O)OC(C)(C)C)C1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: OCc1ccccc1
Product: COC(=O)[C@@H]1C[C@H](N)CN(C(=O)OC(C)(C)C)C1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
(3S,5R)-1-(tert-Butoxycarbonyl)-5-(methoxycarbonyl)piperidine-3-carboxylic acid (2.83 g) was suspended in toluene (36 ml), diphenylphosphoryl azide (2.60 ml) and triethylamine (1.70 ml) were added and the mixture was stirred at 100° C. for 1 hr. The reaction mixture was cooled to room temperature, benzyl alcohol (1.53 ml) and triethylamine (7.00 ml) were added and the mixture was stirred at 80° C. for 3 hr. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate. The mixture was washed with water, 0.5 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine in this order, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography. The fraction eluted with ethyl acetate-hexane (1:3-3:1) was concentrated under reduced pressure. The obtained residue was dissolved in methanol (60 ml), 10% palladium-carbon (50% containing water) (150 mg) was added, and the mixture was subjected to catalytic reduction at ambient temperature under a hydron atmosphere (1 atm) for 5 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (1.83 g) as an oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([C:10]3([C:13]([OH:15])=[O:14])[CH2:12][CH2:11]3)[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1>CO.O=[Pt]=O>[O:1]1[C:5]2[CH:6]=[C:7]([C:10]3([C:13]([OH:15])=[O:14])[CH2:12][CH2:11]3)[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=C(O)C1(c2ccc3ccoc3c2)CC1
Agent: O=[Pt]=O
Solvent: CO
Product: O=C(O)C1(c2ccc3c(c2)OCC3)CC1
Temperature: 20 °C
Reaction time: 72 h
Yield: 42.2 %

Procedure:
To a solution of 1-(benzofuran-6-yl)cyclopropanecarboxylic acid (370 mg, 1.8 mmol) in MeOH (50 mL) was added PtO2 (75 mg, 20%) at room temperature. The reaction mixture was stirred under hydrogen atmosphere (1 atm) at 20° C. for 3 d. The reaction mixture was filtered and the solvent was evaporated in vacuo to afford the crude product, which was purified by prepared HPLC to give 1-(2,3-dihydrobenzofuran-6-yl)cyclopropanecarboxylic acid (155 mg, 42%). 1H NMR (300 MHz, MeOD) δ 7.13 (d, J=7.5 Hz, 1 H), 6.83 (d, J=7.8 Hz, 1 H), 6.74 (s, 1 H), 4.55 (t, J=8.7 Hz, 2 H), 3.18 (t, J=8.7 Hz, 2 H), 1.56-1.53 (m, 2 H), 1.19-1.15 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[NH:29])=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1.N1C=CC=CC=1.[Cl:37][CH2:38][C:39](Cl)=[O:40]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[N:29][C:39](=[O:40])[CH2:38][Cl:37])=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1
Reactant: CS(=N)(=O)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Reactant: O=C(Cl)CCl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=NC(=O)CCl)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Yield: 55.6 %

Procedure:
To a stirring solution of S-[4-(N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]-4-chlorophenyl}carbamoyl)phenyl]-S-methyl sulfoximide (0.5 g, 0.001 mol) and pyridine (2 mL) in DCM (20 mL) was added Chloroacetyl chloride (244 mg, 0.00215 mol) at 0° C. After few minutes, reaction mixture was diluted with water (10 ml). Organic layer was separated, dried and distilled out to get 300 mg of desired product in 52% yield.
Reaction SMILES: [CH3:1][I:2].[NH2:3][C:4]1[S:5][C:6]([CH3:9])=[N:7][N:8]=1>C(O)(C)C>[IH:2].[NH:3]=[C:4]1[N:8]([CH3:1])[N:7]=[C:6]([CH3:9])[S:5]1
Reactant: Cc1nnc(N)s1
Reactant: CI
Solvent: CC(C)O
Product: Cc1nn(C)c(=N)s1
Product: I

Procedure:
64.1 g of methyl iodide are added to a solution of 17.6 g of 2-amino-5-methyl-1,3,4-thiadiazole in 350 ml isopropanol. The solution is refluxed for 15 hours. The reaction mixture is then evaporated to dryness, the crystalline evaporation residue is stirred with ethyl acetate and the solvent is filtered off with suction. The crystalline residue is washed, first with ethyl acetate and then with ether, and then dried. 2-Imino-3,5-dimethyl-4-(1,3,4) -thiadiazoline hydroiodide with a melting point of 208° (decomposition) is thus obtained.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([F:12])=[C:7]([CH2:9][CH2:10][OH:11])[CH:8]=1.FC(F)(F)C(O)=O.[CH:20]([C:23]1[S:24][CH:25]=[C:26]([C:28]([N:30]2[CH2:35][C:34]3([CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[O:33][CH2:32][CH2:31]2)=[O:29])[N:27]=1)([CH3:22])[CH3:21].C(N(CC)CC)C>C(#N)C>[F:12][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][N:38]2[CH2:39][CH2:40][C:34]3([O:33][CH2:32][CH2:31][N:30]([C:28]([C:26]4[N:27]=[C:23]([CH:20]([CH3:21])[CH3:22])[S:24][CH:25]=4)=[O:29])[CH2:35]3)[CH2:36][CH2:37]2)=[CH:8][C:7]=1[CH2:9][CH2:10][OH:11]
Reactant: OCCc1cc(CBr)ccc1F
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4ccc(F)c(CCO)c4)CC3)C2)cs1
Reaction time: 8 h

Procedure:
2-(5-(Bromomethyl)-2-fluorophenyl)ethanol (example 47, step a) (0.16 g) was added to a solution of (2-isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 22, step b) (0.3 g) and triethylamine (0.3 mL) in acetonitrile (10 mL). The resulting mixture was stirred overnight, diluted with acetonitrile (20 mL) and applied to a SCX cartridge (10 g Varian, pre-wetted with acetonitrile (50 mL)). The cartridge was washed with acetonitrile (50 mL) and eluted with 10% ‘880’ aqueous ammonia in acetonitrile solution (50 mL). The eluent was evaporated, azeotroped with toluene and purified by silica gel chromatography eluting with 77.5:17.5:5 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine gradient. The fractions containing product were combined and evaporated to give to the subtitled compound as a yellow gum. Yield 0.22 g.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1.[NH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][N:21]=[CH:20]2>>[NH:22]1[C:23]2[C:19](=[CH:18][CH:17]=[CH:16][C:15]=2[NH:14][C:2]2[N:7]=[C:6]([NH:14][C:15]3[CH:16]=[CH:17][CH:18]=[C:19]4[C:23]=3[NH:22][N:21]=[CH:20]4)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=2)[CH:20]=[N:21]1
Reactant: Nc1cccc2cn[nH]c12
Reactant: CCOC(=O)c1cnc(Cl)nc1Cl
Product: CCOC(=O)c1cnc(Nc2cccc3cn[nH]c23)nc1Nc1cccc2cn[nH]c12

Procedure:
In like manner to N2,N4-bis(3-hydroxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine, 2,4-dichloro-5-ethoxycarbonylpyrimidine and 7-aminoindazole were reacted to yield N2,N4-bis(7-indazolyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 8.70 (s, 1H), 7.54 (d, 2H J=8.4 Hz), 7.37 (m, 6H), 4.3 (q, 2H, J=7.0 Hz), 1.33 (3H, J=7 Hz); LCMS: ret. time 23.61 min.; purity: 94%; MS (m/e): 415 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([CH3:24])([O:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[C:11]([CH3:17])[NH:12]2)[CH3:6])[CH3:2].[CH2:26](Br)[CH2:27][CH3:28]>>[CH2:1]([O:3][C:4](=[O:25])[C:5]([CH3:24])([O:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[C:11]([CH3:17])[N:12]2[CH2:26][CH2:27][CH3:28])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cccc2[nH]c(C)c(-c3ccccc3)c12
Reactant: CCCBr
Product: CCCn1c(C)c(-c2ccccc2)c2c(OC(C)(C)C(=O)OCC)cccc21

Procedure:
The above compound was prepared from 2-methyl-2-[2-methyl-3-phenyl-1H-indole-4-yloxy]-propanoic acid ethylester and propylbromide using a procedure analogous to that of Example 63.
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][CH:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[N:8]([CH3:13])[C:7]([CH3:15])([CH3:14])[CH2:6]1.[C:17]([OH:21])(=[O:20])[CH:18]=[CH2:19]>C1(C)C(C)=CC=CC=1.[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[C:17]([O:21][CH2:16][CH:2]([OH:1])[CH2:3][O:4][CH:5]1[CH2:6][C:7]([CH3:14])([CH3:15])[N:8]([CH3:13])[C:9]([CH3:12])([CH3:11])[CH2:10]1)(=[O:20])[CH:18]=[CH2:19]
Reactant: CN1C(C)(C)CC(OCC2CO2)CC1(C)C
Reactant: C=CC(=O)O
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: Cc1ccccc1C
Product: C=CC(=O)OCC(O)COC1CC(C)(C)N(C)C(C)(C)C1
Temperature: 0 °C
Yield: 43 %

Procedure:
375 g (1.65 mol of (4-(2,3-epoxypropoxy)-1,2,2,6,6-pentamethylpiperidine (=A1a) in 1.5 l of xylene are introduced under argon into a 2.5 l sulfonation flask fitted with magnetic stirrer, thermometer and condenser. 108 g (1.5 mol) of acrylic acid and 27.8 g (75 mmol) of ethyltriphenylphosphonium bromide are added. The reactants are allowed to react at 70° C. for 18 hours. The cooled product is poured into ice water, and the organic phase is separated off, washed twice with 1N sodium hydroxide solution, dried and evaporated. The residue is distilled over a short Vigreux column. 193 g (43%) of the title product are obtained as a clear liquid of boiling point 119°-125° C. (0.06 mm Hg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:29][CH3:30])=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:9](=[O:28])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=2)=[CH:13][CH:12]=1.[H-].[Na+].Cl[C:34]([O:36][CH3:37])=[O:35]>O1CCCC1>[Cl:1][C:2]1[C:3]([CH2:29][CH3:30])=[N:4][CH:5]=[CH:6][C:7]=1[N:8]([C:34]([O:36][CH3:37])=[O:35])[C:9](=[O:28])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:20][N:19]=2)=[CH:15][CH:16]=1
Reactant: CCc1nccc(NC(=O)Cc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)c1Cl
Reactant: COC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1nccc(N(C(=O)Cc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)C(=O)OC)c1Cl
Temperature: 25 °C
Yield: 28.3 %

Procedure:
0.87 g (2.0 mmol) of N-(3-chloro-2-ethylpyridin-4-yl)-4-[(5-trifluoromethylpyridin-2-yl)oxy]phenylacetamide was dissolved in 5 ml of tetrahydrofuran, and the solution was stirred at room temperature. Then, 0.058 g (2.4 mmol) of sodium hydride was gradually added thereto, and the mixture was further stirred for one hour at room temperature. Then, 2 ml of a tetrahydrofuran solution containing 0.38 g (4.0 mmol) of methyl chloroformate was dropwise added thereto at a temperature of from -5° to 0° C, and the mixture was stirred for 30 minutes at a temperature of from -5° to 0° C. and for 12 hours at room temperature. Then, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. Then, ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate) and then purified by high performance liquid chromatography to obtain 0.28 g of the desired product as a white powder (melting point: 62° to 64° C.)